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Dasatinib inhibits site-specific tyrosine phosphorylation of androgen receptor by Ack1 and Src kinases

Y Liu1, M Karaca, Z Zhang

  • 1UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295, USA.

Oncogene
|April 13, 2010
PubMed

Insights

Specific tyrosine kinases phosphorylate the androgen receptor (AR) at distinct sites, influencing castration-resistant prostate cancer growth. The drug dasatinib shows potential antitumor activity by inhibiting both Ack1 and Src kinases.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Androgen receptor (AR) activation plays a role in castration-resistant prostate cancer (CRPC).
  • Tyrosine kinases Ack1 (activated cdc42-associated kinase) and Src phosphorylate and activate AR, promoting tumor growth.
  • Upstream signals activating these kinases in AR signaling are not fully understood.

Purpose of the Study:

  • To investigate AR phosphorylation in response to non-androgen ligands.
  • To elucidate the roles of Ack1 and Src in AR activation by specific growth factors and cytokines.
  • To evaluate the therapeutic potential of dasatinib in prostate cancer models.

Main Methods:

  • Stimulation of LNCaP and LAPC-4 prostate cancer cells with epidermal growth factor (EGF), heregulin, Gas6, interleukin-6 (IL-6), or bombesin.
  • Use of phospho-specific antibodies to detect AR phosphorylation at Tyr-267 and Tyr-534.
  • Small interfering RNA (siRNA)-mediated knockdown of Ack1 and Src.
  • Inhibition studies using dasatinib, a Src inhibitor with potential Ack1 inhibitory activity.
  • Assessment of AR-dependent reporter activity and gene expression.
  • Evaluation of dasatinib's effect on colony formation and prostate xenograft tumor growth in castrated mice.

Main Results:

  • EGF, heregulin, and Gas6 induced AR phosphorylation at Tyr-267, mediated by Ack1 (for heregulin/Gas6) or an unknown kinase (for EGF).
  • EGF, IL-6, and bombesin induced AR phosphorylation at Tyr-534, mediated by Src.
  • Dasatinib inhibited EGF-induced Tyr-534 phosphorylation, Ack1 kinase activity, and AR Tyr-267 phosphorylation.
  • Dasatinib treatment suppressed AR-dependent reporter activity, gene expression, colony formation, and prostate tumor growth in vivo.
  • EGF-induced AR Tyr-267 phosphorylation was not inhibited by Ack1/Src knockdown or dasatinib, suggesting alternative pathways.

Conclusions:

  • Specific tyrosine kinases phosphorylate the androgen receptor at distinct sites, influencing prostate cancer progression.
  • Dasatinib demonstrates significant antitumor activity in preclinical models, likely through concurrent inhibition of Ack1 and Src kinases.
  • Targeting these specific phosphorylation events represents a potential therapeutic strategy for castration-resistant prostate cancer.

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